Glutamine and asparagine activate mTORC1 independently of Rag GTPases

被引:154
|
作者
Meng, Delong [1 ,2 ,3 ]
Yang, Qianmei [1 ,2 ,3 ]
Wang, Huanyu [1 ,2 ,3 ]
Melick, Chase H. [1 ,2 ,3 ]
Navlani, Rishika [1 ,2 ,3 ]
Frank, Anderson R. [1 ,2 ,3 ]
Jewell, Jenna L. [1 ,2 ,3 ]
机构
[1] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, 6000 Harry Hines Blvd,Rm NA5-508A, Dallas, TX 75390 USA
[2] Univ Texas Southwestern Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA
[3] Univ Texas Southwestern Med Ctr Dallas, Hamon Ctr Regenerat Sci & Med, Dallas, TX 75390 USA
基金
美国国家卫生研究院;
关键词
amino acid; glutamine; mTOR complex (mTORC); metabolism; signal transduction; ADP-ribosylation factor 1 (Arf1); asparagine; mTORC1; Rag GTPase; amino acid sensing; v-ATPase; lysosome; metabolic regulation; TUBEROUS SCLEROSIS COMPLEX; AMINO-ACID SUFFICIENCY; TUMOR-SUPPRESSOR; REGULATES MTOR; DIRECT TARGET; GAP ACTIVITY; PROTEIN; METABOLISM; MECHANISM; UPSTREAM;
D O I
10.1074/jbc.AC119.011578
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Nutrient sensing by cells is crucial, and when this sensing mechanism is disturbed, human disease can occur. mTOR complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Leucine, arginine, and methionine signal to mTORC1 through the well-characterized Rag GTPase signaling pathway. In contrast, glutamine activates mTORC1 through a Rag GTPase?independent mechanism that requires ADP-ribosylation factor 1 (Arf1). Here, using several biochemical and genetic approaches, we show that eight amino acids filter through the Rag GTPase pathway. Like glutamine, asparagine signals to mTORC1 through Arf1 in the absence of the Rag GTPases. Both the Rag-dependent and Rag-independent pathways required the lysosome and lysosomal function for mTORC1 activation. Our results show that mTORC1 is differentially regulated by amino acids through two distinct pathways.
引用
收藏
页码:2890 / 2899
页数:10
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